6-methylated and 11-oxygenated-17 alpha-hydroxy-21-fluoro 4-pregnene 3, 20 diones



United States Patent 6-METHYLAT-ED AND 11-OXYGENATED-17ot-HY-DROXY-Zl-FLUORO 4-PREGNENE 3,20 DIONES Frank H. Lincoln, Jr., Kalamazoo,and William P. Schneider and George B. Spero, Kalamazoo Township,Kalamazoo County, Mich., assignors to The Upjohn Company, Kalamazoo,Mich., a corporation of Michigan No Drawing. Application November 23,1956 Serial No. 623,763

5 Claims. (Cl. v260397.45)

' The present invention relates to steroid compounds and is concernedwith -hydrocarbyl substituted steroid compounds, particularly with6-methyl-l1B,17a-dihy-droXy 2lfluoro-4-pregnene-3,20-dione, theintermediate 6-methyl- 115,170; dihydroxy 21 iodo 4 pregnene 3,20 dione,6 methyl 17a hydroxy 21 fiuoro 4 pregnene- 3,11,20-trione and a processfor the production therefor.

The new compounds and the process of the present invention areillustratively represented by the following formulae:

CH CH3 CHzOH (IJHtOSmR 3:0 C: ---0H on HO HO CH3 ClHs CE: I CH3 II CH1CH3 (EH21? (IJH I C=O C ----0H '"OH CH3 CH3 l CH3 IV CH1 III clHzF C=O---o11 CH5 0: j

1 CH3 V wherein R is an organicradical such as methyl, ethyl, phenyl,.tolyl, naphthyl, or the like, with methyl preferred. 1 Theprocess ofthe present invention comprises treating6-methyl-l1B,170:,21-trihydroxy-'4-pregnene-3 ,20-dione(6-methylhydroc-ortisone, I) with an organic sulfonyl 2,867,631 PatentedJan. 6, 1959 halide such as methanesulfonyl chloride, toluenesulfonyl,chloride, toluenesulfonyl bromide, benzenesulfonyl chloride,naphthylsulfonyl chloride, or the like, to obtain the correspondingester (11), a 21-sulfonate of 6-methyl-11,17ut,21-trihydroxy-4-pregnene-3,20-dione; treating the thus produced2l-alkyl or aryl sulfonate of 6-methyl- 115,17 01,21 trihydroxy 4.pregnene 3,20 dione with sodium iodide in acetone solution to obtain6-methy1- l 1B,17u-dihydroxy-21-iodo-4-pregnene-3,20-dione (III)treating the thus obtained 6-methyl-11;3,1'Zot-dihydroxy-21-iodo-4-pregnene-3,20-dione with silver fluoride, preferably inacetonitrile solution to obtain 6-methy1-11p, 17 a .dihydroxy 21 fiuoro4 'pregnene 3,20 dione (1V), and if desired oxidizing the thus obtained6-methy1- 1 1p, l7ot-dihydroxy-2 l-fluoro-4-pregnene-3,20-dione withchromic anhydride, N-bromoacetamide, N-bromosuccinimide, or the like, togive .6-methyl-l7u-hydroxy-2l-fluoro- 4-pregnene3.,11,20-trione (V).

It is an object of the instant invention to provide 6 methyl 115,17dihydroxy 21 fluoro 4 pregnene-3,20-dione and6-.methyl-17u-hydroxy-21-fluoro-4- pregnene-3,1l,20-trione and inparticular, the 6a-epimers, 6a methyl 11,8,17a dihydroXy 21 fiuoro 4pregnene-3,20-dione and 6ot-methyl-17u-hydroxy2l-fluoro-4-pregnene'3,ll,'20-trione. It is another object of the instant inventionto provide a process for the preparation of6-methyl-l1fl,l7a-dihydroxy-2l-fiuoro-4-pregnene- 3,20-dione, theintermediate 6-methyl-llfi,l7u-dihydroxy- 21 iodo 4 pregnene 3,20 dione,and 6 methyl. 171x hydroxy 21 fluoro 4 pregnene 3,11,20 trione. Otherobjects of this invention will be apparent to those skilled in the artto which this invention pertains.

The novel 6ct-mfilhyi-l113,17ot-dihYdlOXY-21-fillOlIO-4-pregnene-3,20-diones and the6a-methyl-l7a-hydroxy-2lfluoro-4-pregnene-3,11,20-triones possess a highorder ofphysiological activities, and possess activity spectra differentfrom the adrenocortical hormones found in nature such as hydrocortisoneand cortisone especially in their effect on mineral and watermetabolism. These com pounds cause a loss of salt and water which makesthem especially valuable in the management of .chronic congestive heartfailure and in the treatmentof cirrhosis of the liver, the nephroticsyndrome and the treatment of eclampsia and preeclampsia. The novelsynthetic corticosteroid hormones of the present invention also possessanti-inflammatory, glucocorticoid, anesthetic, uterine, ovarial andadrenal growth-depressional, and adrenal corticoid activity. Theanti-inflammatory activity is notable in all the streoids of the presentinvention. The 613-epimers, 6fi-methyl-l1,3,17a-dihydroXy-21-fluoro-4-pregnene-3,20-dione and 65- methyl-17a-hydroxyr21-fluoro-4-pregnene-3,11,20rtriones have the same activity as the6u-epimers.

The novel 6-methyl-l1,8,17u-dihydroxy-21-fluoro-4- pregnene 3,20 dionesand 6 methyl 17a hydroxy- 21-fluoro-4-pregnene-3,11,20-triones .areuseful vin 'oral, parenteral and topical compositions. In oralcompositions the materialmay be given as tablets illustratively usingeither polyethylene glycol 4000 or 6000 as a carrier or lactose and/orsucrose as a diluent. The'novel 6a methyl 11 8,1711 ---dihydroXy 21fluoro 4 --preg nene-3,20-dione andvmat-methyl-l7ot-hydroxy-2l-fluoro-4- pregnene-3,1l,20?trione are alsouseful for topical application asointments, lotions, jellies, creams,suppositories, bougies, aqueous suspensions etc. Examples of especiallyadvantageous topical preparations of suitable compositions ,are givenbelow. While the examples are illustrative for the6a-methyl-1lfi,l'7ot-dihydroxy-2l-fiuoro-4- pregnene 3,20 dione and 60amethyl 17oz -;hydroxy- 2l-fluoro-4-pregnene-3,1l,20trione, equivalentamounts of 6;? methyl 115,170; dihydroxy 21 fluoro '4- Lbs.

Wool fat USP 100 Mineraloil USP 125 6a methyl 1113,1711 dihydroxy 21fluoro-4- pregnene-3,20-dione (micronized) White petrolatum USP 500Incorporation of an antibiotic in the ointment, espe I cial ly neomycinsulfate. has therapeutic advantages, each active ingredient potentiatingand supplementing the useful properties of the other. Such an ointmentis as In place of, or in addition to, neomycin sulfate, otherantibiotics such as bacitracin, circulin, polymyxin B sulfate,gramicidin, streptomycin sulfate, dihydrostreptomycin sulfate,oxvtetracycline. chlorotetracvcline, tetracycline, chloramphenicol andthe sulfonamides can be used in conjunction with the steroids of thepresent invention in preparations such as the above ointments.

The com ounds of the instant invention, 6-methyl- 116,170:dihydroxy-21-fluoro-4-pregnene-3.20-dione and the ll-keto analoguesthereof are also useful as starting materials for the preparation ofother physiologically important compounds. such as the 9a-haloanalogues, especially 6a-methyl-9a,2l-difiuoro-l 113,17oc-d1hYdIOXY-4-pregnene-3.20-dione and 6a-methyl-9u,2l-difluoro l7uhydroxy-4-prenene-3,11.20-trione which can be prepared as shown in Exam les 11 and12. The halo derivatives, 6a methyl-9a,21-difluoro-l113.17a-dihydroxy-4-pregnene- 3,20-dione and6u-methyl-9a,2l-difiuoro-l7a hydroxy-4- presnene-3,l1,20-trione arecompounds having glucocorticoid and anti-inflammatory activity and maybe used instead or with 6u-methvl-118,17a-dihydroxy-4-pregnene-3.20-dione and 6m-methyl-l7a-hydroxy-4-pregnene-3,11, 20-trione in theabove pharmaceutical compositions.

The startingcompounds of the instant invention are6-methylhydrocortisone (6a and dfl-isomers) or other6-alkylhydrocortisones prepared as shown in Preparations 1 through 9.

In carrying out the process of the instant invention,6-methylhydrocortisone (6ozor 6 3-methylhydrocortisone) is treated withan acid halide of a sulfonic acid such as methanesulfonic acid,ethanesulfonic acid, propanesulfonic acid, benzenesulfonic acid,,B-toluenesulfonic acid, dand B-naphthanesulfonic acid, or the like,with methanesulfonic acid halides, especially methanesulfonyl chloride,preferred. In the preferred embodiment of the instant invention, thesteroid is usually reacted with the alkylor arylsulfonyl halide insolution in a solvent such aspyridine, benzene, toluene, or the like ata temperature between minus ten and plus sixty degrees centigradeproviding that at the lower temperature the reaction mixture has notsolidified. Thus for pyridine, dioxane, toluene, or the like, temeratures around zero to ten degrees may be used, while for benzene onlytemperatures above five degrees are suitable on account of its.relatively high melting point. The time of reaction is. usually betweenthirty minutes and six or eight hours after which the product,6-methyl-l1fi,17oc,21-trihydroxy- 4-pregnene-3,20-dione 21-alkylorarylsulfonate is removed in conventional manner, for example, byevapqrat ing the solvent until a dry residue is precipitated or byextracting the material from an aqueous solution. For extraction,solvents such as methylene dichloride, chloroform, carbon tetrachloride,benzene, ether, toluene, or the like may be used. Removing theextraction solvent by distillation leaves the6-methyl-1lfl,l7a,2l-trihydroxy- 4-pregnene-3,20-dione 2l-alkylorarylsulfonate.

From the thus-obtained 6 methyl 11B,17a,21trihydroxy-4-pregnene-3,20-dione 21-alkylor arylsulfonate withoutfurther purification 6-methyl-11,8,17a-dihydroXy-21-iodo-4-pregnene-3,20-dione is prepared by reacting the alkylorarylsulfonate of 1119,17a,21-trihydroxy-4-pregnene-3,20-dione, dissolvedin acetone, with sodium or potassium iodide at reflux temperature.Excess of sodium iodide is generally preferred and the reaction mixtureis refluxed for a period of three or four minutes to half an hour. Thethus produced 6-methyl-11;3,17a-dihydroxy-Z1-iodo-4-pregnene-3,20-dioneis obtained from the reaction mixture by evaporating the solvent and canbe used without further purification for the preparation of6-methyl-11p,17a-dihydroxy-21-fluoro4-pregnene-3,20- dione.

The ZI-iodo compound, 6-methyl-llfl,l7a-dihydroxy-21-iodo-4-pregnene-3,20-dione, dissolved in a suitable solvent such asacetonitrile, hexanes, heptanes, benzene, tertiary butyl alcohol, or thelike with acetonitrile preferred, is then reacted with silver fluoride.The reaction is usually carried out under exclusion of light and withstirring. The preferred form of silver fluoride used is a fifty percentaqueous silver fluoride solution rather than solid silver fluoride. Thereaction is preferably carried out between forty to sixty degreescentigrade, however, lower or higher temperatures between ten and about75 degrees centigrade are operative. Since the silver iodide produced inthe reaction forms a molecular compound With silver fluoride, two molesof silver fluoride must be used per mole of steroid as the minimumamount necessary for theoretical recovery. However, it is preferred touse an even greateramount, between ten to fifty percent over and abovethe calculated amount, in order to obtain higher yields. The silverfluoride is usually added in portions over a period of time. Thereaction time ranges from one half to six hours. In order to isolate theproduct, 6 methyl 11,8,17a dihydroxy 21 fluoro- 4-pregnene-3,20-dione,the solvent is evaporated and the crude product extracted with asuitable solvent such as chloroform, methylene chloride, carbontetrachloride, benzene, or the like. Purification is made byconventional procedures such as additional extraction to eliminateimpurities, recrystallization, or chromatography, as deemed necessary.

The oxidation of 6-methyl-11 8,17a-dihydroxy-21-fluoro-4-pregnene-3,20-dione is generally carried ,out in conventional mannersuch as, for example, oxidizing the 6- methyl 1113,1701 dihydroxy 21fluoro 4 pregnene-3, 20-di0ne in acetic acid solution with chromicanhydride using a calculated amount of chromic anhydride or a slightexcess such as from ten to thirty percent excess of the calculatedamount, or oxidizing the 11B,17a-dihy-'droxy-21-fluoro-4-pregnene-3,20-dione with a N-halo amide orN-haloimide of an acid such as, N-bromoacetamide, N-chlorosuccinimide,N-bromosuccinimide, or the like, in pyridine, dioxane, or other solventsolutions. After termination of the oxidation the oxidant is generallydestroyed such as by addition of methyl alcohol, ethyl alcohol, andother alcohols when chromic anhydride was used or bisulfite for bothchromic anhydride and N-haloacidamides and N-haloacidimides. Thereafter,the product 6-methyl-l7a-hydroxy-2l-fluoro-4-pregnene-3,11,20-trione isisolated by conventional means such as extraction with Water-immisciblesolvents, for example, methylene chloride, ethylene chloride,chloroform, carbon tetrachloride, ether, benzene, toluene, or the like,or by chromatography, if deemed necessary.

The following examples are illustrative of the process construed aslimiting.

PREPARATION l 5 11,6 a-oxido-I 1 {3,1 7a,21-trihydroxyallapregnane-3,20-

dione 3,20-bis-(ethylene ketal) To a solution of 0.901 gramof11fi,'17ot,21-trihydroxy- 4-pregnene-3,20-dione 3,20-bis-(ethyleneketal) in eighteen milliliters of chloroform was added a solution of 331milligrams of perbenzoic acid in 5.19 milliliters of chloroform. Theresulting solution was allowed to stand in the refrigerator (ca. fourdegrees centigrade) for a period of 24 hours and thereupon at roomtemperature for an additional period of 72 hours. The reaction solutionwas then washed with five percent sodium bicarbonate solution and water,dried over anhydrous sodium sulfate and evaporated to dryness to give1.031 grams of crude solid. Recrystallization from acetone gave 431milligrams of material of melting point 230 to 247 degrees centigrade.The mother liquor, after evaporation to dryness, was dissolved inmethylene chloride and chromatographed over 25 grams of acid washedalumina. The column was developed with three fractions each of methylenechloride plus five, ten, fifteen, twenty, twenty-five and fifty percentacetone, acetone, and acetone plus five percent methanol. The acetoneplus five percent methanol eluate gave an additional 279 milligrams ofthe high melting product. The high melting material,50,6a-0Xid0-11B,l7ot,21-trihydroxyallopregnane-3,20-dione3,20-bis-(ethylene ketal) was three times recrystallized from acetoneand methanol to give a pure product of melting point 263 to 2 68 degreescentigrade. Other eluate fractions of lower melting point contained the5 5,6,8-isomer thereof.

PREPARATION 2 5a,6a-0xid0-17a,21-dihydroxypregnane-3J1,20-tri0ne3,20-bis-(1,2-prpylene ketal) To a solution of one gram ofl7u,21-dihydroxy-5- pregnene-3,1l,20-trione -3,20-bis-(1,2-propyleneketal) [cortisone 3,20-bis-(1,2-propylene ketal)] in chloroform wasadded a solution of perbenzoic acid in chloroform and the resultingsolution allowed to stand in a refrigerator and then at roomtemperature, following the procedure of Preparation 1. The reactionsolution was washed, dried, and evaporated as in Preparation 1.Recrystallization from acetone followed by fractionation of the motherliquor on a column of acid washed alumina, using the technique ofPreparation 1, yielded a,6ot-oxido- 17,21-dihydroxyallopregnane-3,1 1,20trione 3,20 bis- (1,2-propylene ketal) and the 55,6{3-oxido isomer.

Using as starting material in Preparation 2, the more commonly availablecortisone 3,20-bis-(ethylene k'etal) gives the5a,6a-oxid-o-'l7a,21-dihydroxyallopregnane- 3,11,20-trione3,20-bis-(ethylene ketal).

In the same manner as shown in Preparations 1 and 2, 50,60toxido-11fl,17ot,21 trihydroxyallopregnane 3,20- dione 3,20-bis-(alkyleneketals) and 5a,6ot-0XlClO-17cx,2ldihydroxyallopregnane -3 ,11,20 trione3 ,20 bis (alkylene ketals) can be prepared by reacting cortisone orhydrocortisone diketa'ls wherein the ketal group has been formed byreacting the steroid 3,20-dione with glycols, such as ethylene,propylene, 1,2- 1,3-, or 2,3-butylene glycol or pentane, hexane,heptane, or octane-diols wherein the alcohol groups are in vicinalpositions such as 1,2, 2,3, 3,4 or the like, or separated by one carbonatom such as 1,3, 2,4, 3,5, and the like, with an organic peracid suchas performic, peracetic, perbenzoic, monoperplithalic acid, or the like.For the purpose of this invention, starting compounds having theethylene ketal groups are preferred, since these ketals are generallymore easily prepared in high yield than ketals produced by the reactionof the 3,20-diketo compounds with higher 'alkanediols.

PREPARATION 3 5 0a,] 1 5,170:,21-tetrahydnoxy-6B-methylall0pregriane-3,2O-

dione 3,20-bis-(ethylene ketal) A solution of 1.115 grams of5a,6oc0Xid0-lllB,l7ot,2 ltrihydroxyallopregnane-3,ZO-dione3,20-bis-(ethylene ketal) in 165 milliliters of tetrahydrofuran (thetetrahydrofuran being dried through distillation over lithium aluminumhydride) was added dropwise to a solution of milliliters of methylmagnesium bromide in ether (the magnesium bromide having a four molarconcentration). To this mixture Was added 575 milliliters of benzene andthe reaction mixture was thereupon allowed to stir and reflux for 26hours. After cooling, the reaction mixture was poured into 700milliliters of iced, saturated ammonium chloride solution, stirred for aperiod of thirty minutes, and the benzene layer separated from theaqueous layer. The aqueous phase was extracted with three ZOO-milliliterportions of ethyl acetate and the extracts added to the benzene layer.The combined benzene-ethyl acetate solution was thereupon washed withwater, dried over anhydrous sodium sulfate and evaporated to dryness togive 1.314 grams of crude solid. Trituration of this material with etherleft 1.064 grams of crystalline product of melting point 221 to 230degrees. Recrystallization of this material gave5a,1'15,17a,21-tetrahydroxy-6p-methylallopregnane-3,20-dione3,20-bis-(ethylene ketal) of melting point 228 to 233 degrees androtation [ocl minus eleven degrees in chloroform.

Analysis.-Calcd. for C H O C, 64.70; H, 8.77. Found: C, 64.29; H, 8.69.

PREPARATION 4 5 11,1113,17a,21-tetrahydr0acy-6,B-ethylallopregnane-3,20- dione3,20-bis-(ethylene ketal) 20-bis-(ethylene ketal) oxygenated in thell-position.

with a metal alkyl or metal aryl more specifically an alkyl metal halidesuch as a Grignard reagent, for example, methyl, ethyl, propyl,isopropyl, butyl, pentyl, hexyl, and phenyl magnesium bromides andiodides or cadmium alkyl and calcium alkyl and phenyl bromides oriodides. Representative 6p-alkylated allopregnanes thus preparedinclude: 5u,11/3,17a,21-tetrahydroxy-6;3- propylallopregnane-3,20-dione3,20-bis-(ethylene ketal), 50,11fi,17a,21-tetrahydroxy 65butylallopregnane-3,20- dione 3,20-bis-(ethylene ketal),5a,11fl,17a,21-tetrahydroxy-6;3-isobutylallopregnane-3,20-dione3,20-bis-(ethylname-3,20-dione 3,20-bis-(ethylene ketal),50:,11,B,17a,2ltetrahydroxy-6/3-hexylallopregnane-3,20-dione 3,20-bis-(ethylene ketal),5a,11fi,17a,21-tetrahydroxy-6p-phenylallopregnane-3,20-dione3,20-bis-(ethylene ketal), 5 ot,17a,21-trihydroxy-6fi-methylallopregnane-3 ,1 1 ,20-trione 3 ,20-bis-(ethylene ketal),5a,17u,2l-trihydroXy-6,8-ethylallopregnane-3,11,20-trione3,20-bis-(ethylene ketal), 5a,17u,21-trihydroxy-6,6-propylallopregnane-3,11,20-trione 3,20- bis-(ethyleneketal), 5a,17a,2l-trihydroxy-6,B-isopropylallopregnane-3,l1,20-trione3,20-bis-(ethylene ketal), 5a, 1701,21-trihydroxy-6,B-butylallopregnane3,11,20 trione 3,20-bis-(ethylene ketal),5oc,l7a,21-trihydroxy-6fl-pentylallopregnane-3,1l,20-trione3,20-bis-(ethylene ketal), 5a, 17a,21-trihydroxy-6fi-hexylallopregnane3,11,20 trione v.5ot,11;8,17ot,2l tetrahydroxy 6B methylallopregnane-3,20-dione A solution was prepared containing 468 milligrams of50:,11/3,17a,21-tetrahydroxy 6,8 methylallopregnane-3, 20-dione3,20-bis-(ethylene ketal), 38 milliliters of methanol and 7.7milliliters of 2N sulfuric acid. This solution was refluxed for a periodof thirty minutes, then neutralized with five percent dilute sodiumbiscarbonate solution (about 100 milliliters) and concentrated underreduced pressure at 55 degrees centigrade to about 35 milliliters ofvolume. A product crystallized upon cooling and was recovered byfiltration. This product was recrystallized from acetone Skellysolve Bhexanes to give an analytical pure sample of50:,1lfl,l7u,2l-tetrahydroxy- 6fi-methylallopregnane3,20-dione ofmelting point 240 to 244 (decomposition) and rotation [al plus fortydegrees in dioxane.

Analysis.Calcd. for C H O C, 66.98; H, 8.69. Found: C, 66.84; H, 8.86.

PREPARATION 6 5a,I1fi,17a,21 tetrahydroxy 6B ethylallopregnane-3,20-dine 20-diones oxygenated in the ll-position, such as for example,50,11B,17a,21-tetrahydroxy 6,8 propylallopreg-- nane-3,20-dione,a,1lB,17a,21-tetrahydroxy-6B-butylallopregnane-3,20-dione,5oc,11,8,17a,21-tetrahydroxy-6/3-isobutylallopregnane 3,20 dione,5a,11fl,17u,21-tetrahydroxy-6,8-pentylallopregnane-3,20-dione,5a,11,6,17a,21- tetrahydroxy-6,8-hexylal1opregnane 3,20 dione, 5a,11[3,170:,21-tetrahydroxy-6fl-phenylallopregnane 3,20 dione,5a,170:,21-trihydroxy-6 8-methylallopregnane 3,11,20-trione, 5a,17,21-trihydroxy-6,3-ethylallopregnane-3,1 1,20- trione,5a,17a,2l-trihydroxy-6B-propylallopregnane-3,1 1, -trione,5a,17a,21-trihydroxy-6fi-isopropylallopregnane- 3,11,20-trione,5a,17a,21-trihydroxy 6,3 butylallopregname-3,11,20-trione,5a,17a,2l-trihydroxy 6B hexylallopregnane 3,11,20 trione, 5a,17ot,21trihydroxy-6fi-- pentylallopregnane-3,11,20-trione, 5a,17u,21-trihydroxy- 6Bphenylallopregnane-3,11,20-trione, and the like,and including those 6 8-alkylallopregnanes having ketal groups inpositions 3 and 20 such as exemplified in Preparation 2.

PREPARATION 7 6ot-metlzylhydrocortisone A stream of nitrogen was bubbledthrough a solution of 429 milligrams of5a,1Ifl,170:,21-t8t13hYd1'0XY-6B- mthylallopregnane-S,20-dione,contained in 100 milliliters of denatured absolute alcohol, for a periodof ten minutes. To this solution was added 4.3 milliliters of 0.1 normalsodium hydroxide solution which had likewise been treated With nitrogen.The mixture was allowed to stand in a nitrogen atmosphere for a periodof eighteen hours and thereupon acidified with acetic acid,

and concentrated under reduced pressure at 55 degrees centigrade todryness. The residue weighing 417 milligrams was recrystallized fromacetone-Skellysolve B hexanes to give in two crops 249 milligrams of6-methylhydrocortisone melting between 184 and 194 degrees centigrade.An analytical sample was prepared melting at 203 to 208 degreescentigrade and consisting of pure 6a-methylhydrocortisone. 1

Analysis.-Calcd. for C H O C, 70.18; H, 8.57. Found: C, 70.32; H, 8.50.

The mother liquors contained besides 6u-methylhydrocortisone,substantial amounts of 6fi-methylhydrocortisone which can be isolated byrecrystallization, papergram, countercurrent procedures and other meansknown in the art.

PREPARATION 8 6fi-methylhydrocortisone A solution was preparedcontaining 27.5 grams of 5vz,11/3,l70c,21 tetrahydroxy 6,8methylallopregnane 3,20-dione in 6500 milliliters of ethanol denaturedwith methanol. The solution was freed of air oxygen by bubblingoxygen-free nitrogen through it for a period of fifteen minutes. To thissolution was added a similarly air oxygen-free prepared solution ofone-tenth normal sodium hydroxide (235 milliliters). The solution wasallowed to stand at room temperature (about 22 to 24 degrees centigrade)in an inert nitrogen atmosphere for a period of twenty hours and Wasthen acidified with fourteen milliliters of acetic acid. The thusobtained acid solution was evaporated at about fifty to sixty degreescentigrade in vacuo, the thus produced residue dissolved in 200milliliters of ethyl acetate and 200 milliliters of water, the waterlayer separated from the organic layer and discarded, the organic layerwashed with 350 milliliters of five percent aqueous sodium bicarbonatesolution, then three times with water and thereupon dried over anhydroussodium sulfate and concentrated to a volume of 180 milliliters.After'cooling the 180 milliliters of solution in a refrigerator (aboutfive degrees centigrade), the solution was filtered giving 11.9 grams ofmaterial. This material was redissolved in 500 milliliters of ethylacetate, the ethyl acetate solution was concentrated to 150 milliliters,refrigerated as before to give 6.15 grams of crude6,8-methylhydrocortisone of melting point 220223.

Recrystallization of the crude 6fi-methylhydrocortisone.

three more times from ethyl acetate gave an analytical sample of6B-methylhydrocortisone with melting point 223 to 227 degreescentrigrade, rotation [aJ plus degrees in acetone; ultravioletabsorption kfgyiethanol y a =l4,5O0.

Analysis.-Calcd. forC I-I O C, 70.17; H, 8.57. Found: C, 70.54; H, 8.91.

PREPARATION 9 6u-ethylhydr0c0rtis0ne In the same manner as shown inPreparation 7, 5a,11 3,l7a,2l tetrahydroxy 6,8 ethylallopregnene3,20-dione was treated with a solution of potassium hydroxide inmethanol to give at room temperature, 60:- ethylhydrocortisone ofmelting point 223-226 degrees centrigrade and In the same mannerdehydrating with an alkali metal hydroxide in alcoholic solution otherll-oxygenated- 5a,17u,2l trihydroxy 6fl-alkylallopregnane-3,ZO-dionesproduced the corresponding ll-oxygenated 6u-alkYl-17a,21-dihydroxy-4-pregnene-3,ZO-diones such as 6u-propylhydrocortisone,6a-butylhydrocortisone, 6otisobutylhydrocortisone,6a-pentylhydrocortisone, 60c hexylyhydrocortisone, or aryl analogues,such as 6OC-PhGI1YIhYdI'OCOI'tISO116, 6amethylcortisone of melting point212.5 to 215 degrees 9\ centigrade, 6u-ethylcortis'one,6a-propylcortisone, 6aisopropylcortisone, 6a-butylcortisone,6a-pentylcortisone, 6a-hexylcortispne, 6 q-pheny lcor tisone, and thelike.

EXAMPLE 1 6a methyl 11;3,17u,21-trihydroxy-4-pregnene-3,20-di0ne 21methanesulfonate (60c methylhydrocortisone 21 methanesulfonate) Asolution was prepared containing one gram (2.65 millimoles) of6a-methylhydrocortisone in seven milliliters of pyridine. This solutionwas cooled to zero degrees-centigrade and treated with 0.3 milliliter ofmethanesulfonyl chloride. Thereafter the solution was allowed to standat zero to five degrees centigrade for a period'oftwo hours, after whichit was diluted with water and extracted with three 25-milliliterportions of methylene' chloride. The extracts were combined, washed withcold dilute hydrochloric acid until a pH of two to three was maintainedin the aqueous layer, then washed again with-cold sodium bicarbonatesolution, water and finally dried over anhydrous sodium sulfate.Evaporation of the methylene chloride extract at reduced pressure gave awhite glassy product of6a-methyl-11fi,17a,2ltrihydroxy-4-pregnene-3,20-dione21-methanesulfonate.

The crude 6u-methyl-1 1 5,17 11,2l-trihydroxyl-pregnene- 3,20-dioneZI-methanesulfonate of Example 1 was dissolved in fifteen milliliters ofacetone and treated with a solution of one gram of sodium iodide in tenmilliliters of acetone. The mixture was heated under reflux withstirring for a period of fifteen minutes, the heat then reduced and themixture concentrated to one third volume at-reduced pressure. Iceandwater were added and the precipitated product collected on a filter,washed with water and dried to yield 1.1 gram of 6u-methyl- 11B,17ocdihydroxy 21 iodo 4 pregnene 3,20 dione of melting point 135 to 140degrees centigrade with decomposition. I

Analysis.:-Calcd. I,"25.05.

for C H O I: I, 26.09. Found:

EXAMPLE 3 6a-methyl-115,17a-dihydroxy-21-fluor0-4-pregnene- 3,20-dine Asolution of one gram of6a-methyl-l1B,17a-dihydroxy-21-iodo-4-pregnene-3,20-dione in 150milliliters of acetonitrile (practical grade) was prepared by heating tothe boiling point. After cooling to forty degrees centigrade, thesolution was protected from light and 0.8 milliliter of fifty percentaqueous solution of silver fluoride was added under stirring. Stirringwas continued for one hour at about forty degrees centigrade, then 0.7milliliter of silver fluoride solution was added and after another hourofistirring another 0.7 milliliter portion of aqueous silver fluoridesolution was added. Heating and stirring was then continued for a periodof two hours. The brown mixture was thereupon filtered through a bed ofCelite diatomaceous earth and the filtrate evaporated at reducedpressure from a bath at a temperature of fifty degrees centigrade. Thebrown residue was thoroughly extracted with two one-hundredmilliliterportions of warm methylene chloride, the combined-extracts washed withwater, dried over anhydrous sodium sulfate and concentrated toapproximately 100- milliliter volumes and chromatographed over 50 gramsof Florisil synthetic magnesium silicate. Fractions of 200 milliliterswere taken as follows:

TABLE I Fractions: Solvent l-9 Hexane-acetone 90:10 10-12 Hexane-acetone85:15 13 n 2 Acetone 100 percent The hexanemixture used was SkellysolveB hexanes; Fractions 5 to 8, inclusive, were combined and evaporated togive 283 milligrams of crystals which after recrystallization fromacetone-Skellysolve B (yielded 260 milligrams) of 6u-methyl-11B,17t-dihydroxy-21-fluoro-4- pregnene-3,20-dione of 220m 223 degreescentigrade.

Analysis.Calcd. for C H O F: C, 69.81; Hz26; F, 5.02 Found: C, 70.14; H,7.95; F, 5.60.

Infrared spectrum in Nujol mineral oil suspension:

Cm.- Hydroxy 3440 ZO-keto 1724 B-keto 1645 A -double bond 1608 EXAMPLE 46 u-methyl-l 7u-hydr0xy-21 -fluor0-4-pregnene-3,1 1 ,20-

trione EXAMPLE 5 Methyl-115,1 7 21-trihydroxy-4-pregnene-3,20-dione 21-toluenesulfonate In the same manner given in Example 1,6a-ethylhydrocortisone, dissolved in pyridine, was treated withtoluenesulfonyl chloride to give 6ot-ethyl-1l,8,l7a,2l-trihydroxy-4-pregnene-3,20-dione 21-toluenesulfonate.

EXAMPLE 6 6 u-ethyZ-I 15,1 7m-dihydr0xy-12-i0d0-4-pregnene-3,20-

' dione In the same manner given in Example 2, reacting6aethyl-11fl,17a,21-trihydroxy-4-pregnene-3,20 dione 21-toluenesulfonate with sodium iodide yielded Got-ethyl-1lB,17ix-dihydroxy21-iodo-4-pregnene-3,20-dione;

EXAMPLE 7 6a-ethyl-1 1 [3,1 7a-dihydr0xy-21 -flu0r0-4-pregnene-3,20dione In the same manner given in Example 3, 6a-ethy1-.11B,17a-dihydroXy-21-iodo-4-pregnene-3,20 dione, dissolved inacetonitrile, was heated with a fifty percent aqueous silver fluoridesolution, to give 6a-ethy1-11 5,17-dihydroxy-21-fluoro-4-pregnene-3,20-dione.

EXA PLE 8 To 200 milligrams Of. 60t-6thy1-11fi,170L-dlhYdI'OXY-21fiuoro-4-pregnene-3,20-dione in eight milliliters of methanol was added0.2 milliliter of pyridine, 0.4 milliliter of water and milligrams ofN-bromoacetamide. The reaction mixture was kept at room temperature fora period of twenty hours and then 25 milliliters of dilute sodiumsulfite solution, was added to destroy excess N-bromoacetarnide. Themixture was thereupon concentrated until copious crystallizationoccurred. The mixture was cooled to zero degrees centigrade and kept atthis temperature for a period of one hour to yield 6a-ethyl-17a-hydroxy21 fluoro-4-pregnene 3,11,20-

t o e l ExaMPLE 9 6ot methyl-17a-hydroxy-21-flu0ro-4-pregnene-3,1I,20-

-' Y trione with potassium iodide in acetone solution results in 6amethyl-17u-hydroxy-21-iodo-4-pregnene-3,11,20 trione; and treating thethus obtained 6a-methyl-l7whydroxy- 2l-iodo-4-pregnene-3,11,20-trione inacetonitrile solution with aqueous silver fluoride solution producesGot-methyl- 170t-hyd1'OXY-21-flUOIO-4-P1'Cgl1EHE-3, 1 1,20-trione.

EXAMPLE 10 In the same mannershown in Example 1, treating other6a-alkylhydrocortisone and 6a-alkylcortisone or the 6maryl analoguesthereof with the chlorides or bromides of toluenesulfonic acid,methanesulfonic acid, and other organic sulfonic acids, give thecorresponding 2l-toluenesulfonate, the ZI-methanesulfonate, or the like21esters of the corresponding 6ot-alkylhydrocortisone, 6u-alkylcortisoneor 6ot-aryl analogues of hydrocortisone and cortisone wherein the alkylgroup may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl,hexyl, or aryl such as phenyl, or the like.

Treating the thus obtained 21-toluenesulfonate, 21- methanesulfonate orother 21-a1kylor 2l-arylsulfonates of 6u-alkylhydrocortisone and6u-alkylcortisone or the 6a-aryl analogues thereof with sodium orpotassium iodide in acetone at elevated temperature, usually refluxtemperature, yields the corresponding 2l-iodo compound such as, forexample, 6a-propyl-1l,8,l7a-dihydr0xy-2liodo-4-pregnene-3,20-dione,6a-isopropyl-11/3,l7u dihydroxy-21 iodo-4-pregnene-3,20-dione, 6a-butyl115,170:- dihydroxy-2l-iodo-4-pregnene-3,20-dione, 6a isobutyl-11,8,17a-dihydroxy-21-iodo-4-pregnene-3,2O dione, 6apentyll1fi,17otdihydroxy-Zl iodo-4-pregnene 3,20- dione,6a-phenyl-11,8,17a-dihydroxy-2l-iodo-4-pregnene- 3,20-dione,6amethyl-l7a-hydroxy-21 iodo-4-pregnene- 3,11,20-t'rione,6u-ethyl-l7a-hydroxy-21-iodo-4-pregnene- 3,11,20-trione, 6a-propyl-17ahydroxy 2l-iodo-4-pregnene-3,1-1,20 -trione,Got-isopropyl-17u-hydroxy-21-iodo-4- pregnene-3,1 1,20-trione,6u-butyl-17a-hydroxy-2l-iodo4- pregnene-3,l1,20-trione,6a-isobutyl-l7a-hydroxy-21-iodo- 4-pregnene-3,l1,20-trione,6OL-pBI1tyl-170t hydroxy 21- iod-4-pregnene-3,11,20-trione,6a-hexyl-17a-hydroxy-21- iodo-4-pregnene-3,l1,20-trione, 6a-phenyl-17ahydroxy- 2l-iodo-4- pregnene-3,l1,20-trione, and the like.

Treating the thus obtained 6a-alkyl-1l 3,17a-dihydroxy-2l-iodo-4-pregnene-3,ZO-diones or 6a-a1kyl-l7a-hydroxy-2l-iodo-4-pregnene-3,11,20-triones or respectively the 60saryl analoguesthereof with aqueous fifty percent silver fluoride solution inacetonitrile as described in Example 3, produces the corresponding6a-alkyl or 6u-aryl-11fi, 17tx-dihydroxy-2l fluoro-4-pregnene3,20-diones' or, respectively, the 6a-alkylor' 6a-aryl-l7u-hydroxy 21-fluoro-4-pregnene-3,l1,20-triones wherein the alkyl group is ethyl,propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or aryl, such asphenyl, or the like.

Instead of u-methylhydrocortisone or cortisone, the 6/3j-epimer can beused in the above examples and if the reaction conditions are kept nearneutral, 6,8-epimers, such as6fi-methyl-llfl,l7u-dihydroxy-2l-fluoro-4-pregnene-3,20-dione and6B-methyl-l7a-hydroxy-21-fluoro-4- pregnene-3,ll,20-trione can beisolated from the reaction mixture. The thus obtained B-epimers yieldthe 60:- epirners by treatment with acid or base in an organic solvent,e; g'., ethanol'at room temperature.

'12 7 EXAMPLE 11 6a-meth yl- 9 oe21 -difluoro 11fl,17u-dihydroxyl Ipregnene-3,20-dione A mixture of one gram of 6a-methyl-llj3,l7a-dihydroxy-Z1-fluoro-4-pregnene-3,ZO-dione, 650 milligrams ofN-bromoacetamide and six milliliters of pyridine were stirred in thedark for a period of thirty minutes. The:

mixture was cooled in an ice-water bath and a stream of sulfur dioxidewas directed onto the surfaceof the stirred mixture until a negativepotassium iodide-starch test was obtained. Fifty milliliters of waterwas then added to the mixture and the mixture was maintained at aboutfive degrees centigrade for thirty minutes. The;

precipitated white solid was filtered, washed with water and dried undervacuum. After crystallizationfrom acetone there was obtained about 0.8gram of 6a-methyl-17mhydroxy-21-fluoro-4,9(11)-pregnadiene-3,20-dione.

0.5 gram of 6a-methyl-17a-hydroxy-21-fluoro-4,9(11)-pregnadiene-3,20-dione was dissolved in twenty milliliters of methylenechloride and thereto was added a solution of one milliliter of 71percent perchloric acid in ten milliliters of water and 200 milligramsof N-bromoacetamide in fifty milliliters of tertiary butyl alcohol. Thesolution was maintained at room temperature for fifteen minutes and thenmixed with a solution of 0.3 gram of sodium sulfite in twelvemilliliters of water. The mixture was distilled at reduced pressureuntil the residual solution became cloudy. The product was thenprecipitated by the addition of milliliters of'a mixture of ice-water.The white crystalline precipitate was filtered, washed with'water andthen dried and recrystallized from a mixture of acetone and SkellysolveB hexane hydrocarbons to give 6tt-methyl-9ot-bromo-ll;6,17o;-dihydroxy-Zl -fluoro-4-pregnene-3,20-dione.

A mixture of 0.45 gram of 6a-methyl-9wbromo-l1p,

17m-dihydroxy-2l-fiuoro-4-pregnene-3,20-dione, 0.45 gram of anhydrouspotassium acetate and twenty milliliters of acetone was heated at itsrefluxing temperature forja: period of five hours. The mixture wasthen'cooled ,and' poured into water and extracted with methylenechloride. and poured over The methylene chloride extract was dried acolumn of 25 grams of Florisil synthetic magnesium silicate. The columnwas developued with Skellysolve B.

hexane hydrocarbons containing increasing portions of acetone. TheSkellysolve B plus ten percent acetone eluate contained6a-methyl-9(11)-oxido-17a-hydroxy-21- fluoro-4-pregnene-3,20-dione. I

A solution of one gram of 6 t-methyl-9(1l)-oxido-I7et Skellysolve Bhexanes to give pure 6ot-methyl-9a,21-'di-;

fiuoro-l1 3,17a-dihydroxy-4-pregnene-3,ZO-dione.

Following the procedure described in Example 11, but substituting other6a-alkylor 6a-aryl-l1/8,17a-dihydroxy- 2l-fluoro-4-pregnene-3,20-dionesfor the 6a-methyl-llfi, 17a-dihydroxy-21-fluoro-4-pregnene-3,20-dionewhereinthe alkyl or, respectively, aryl radical is ethyl, propyl,isopropyl, butyl, isobutyl, pentyl, hexyl, phenyl, or the like, resultsin the corresponding 6a-alkyl9u,2l-dlflIlOI'O-11p,17at-dihydroxy-4-pregnene-3,20-dione wherein the alkyl group will beethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or aryl, suchas phenyl, or the like. 7

EXAMPLE 12 6 a-methyl-9a,21 -d ifluoro-l 7a-hydroxy-4-pregnene- 3,11,20-trine Oxidizing in the manner given in Example 8, 6u-methyl 911,21difluoro 1113,1701 dihydroxy 4 pregnene 3,20-dione with N-bromoacetamidein pyridine solution produces6a-methyl-9a,21-difluoro-17a-hydroxy-4-pregnene-3 ,11,20-trione.

In the manner similar to Example 12, oxidizing with N-bromoacetamide inpyridine solution or with chromic anhydride in acetic acid solution,other 6a-alkylor 611- aryl 90,21 difluoro 1113,1704 dihydroxy 4pregnene-3,20-dione results in the corresponding 6a-alky1- 9a,21difluoro 17o: hydroxy 4 pregnene 3,11,20 triones wherein the alkyl groupis ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, or aryl,such as phenyl, or the like. In the same manner as shown with theGaepimer, the 6,8-epimer may be used as starting material for Examples11 and 12.

This application is a continuation-in-part of copending application S.N. 608,663, now abandoned, filed September 10, 1956.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds shown and described, asobvious modifications and equivalents will be apparent to one skilled inthe art and the invention is therefore to be limited only by the scopeof the appended claims.

We claim:

1. A compound selected from the group consisting of 6 methyl 1113,1701dihydroxy 21 fluoro 4 pregnene-3,20-dione and6-methyl-17a-hydroxy-2l-fluoro-4- pregnene-3 ,11,20-trione.

2. 6 methyl 115,170: pregnene-3,20-dione.

3. 6oz methyl 116,17 dihydroxy 21 fluoro 4 pregnene3,20-dione.

4. 6 methyl 17a hydroxy 21 fluoro 4 pregnene-3,1 1,20-trione.

5. 6a methyl a hydroxy 21 fluoro 4 pregnene-3,11,20-trione.

dihydroxy 21 fluoro 4 References (Iited in the file of this patentUNITED STATES PATENTS 2,684,968 Bergstrom July 27, 1954 2,686,188Johnson Aug. 10, 1954 2,752,369 Holyzz et al June 26, 1956 2,768,191Warnant Oct. 23, 1956 2,786,857 Cutler Mar. 26, 1957 OTHER REFERENCESTannhauser et al.: J. A. C. S., 18, pages 2658-9, June 5, 1956.

Spero et al.: I. A. C. S., 78, pages 6213-14 (1956).

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 6 - METHYL -11B,17A - DIHYDROXY - 21 - FLUORO - 4 - PREGNENE-3,20-DIONE AND6-METHYL-17A-HYDROXY-21-FLUORO-4-EGPREGNENE-3,11,20-TRIONE.